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PubMed1987

Acute and sub-acute inhalation of an organophosphate induce alteration of cholinergic muscarinic receptors.

Acute and sub-acute inhalation exposure of rats to the organophosphorus compound soman (O-[1,2,2-trimethylpropyl]-methylphosphonofluoridate) reduced the contraction of the bronchial smooth muscle induced by cholinergic stimulation. Acute exposure to 8.51 mg/m3 of soman for 45 min (total dose of 383 mg X min/m3) inhibited the acetylcholinesterase (AChE) activity of the bronchial smooth muscle by 85% and reduced the contraction induced by ACh and carbachol by 70% and 80% respectively. In spite of the extensive inhibition of AChE and reduction in the contraction following cholinergic stimulation, there was no alteration of the binding capacity (Bmax) or the equilibrium dissociation constant (Kd) to [3H]-quinuclidinyl benzilate ([3H]-QNB) in the rat bronchi following such an acute exposure. After sub-acute exposure (40 hr) to 0.45-0.63 mg/m3 of soman (total dose of 1080-1519 mg X min/m3) there was a reduction in AChE-activity of 94% and in the contraction of the bronchial smooth muscle induced by ACh and carbachol of 70%. Furthermore, also a reduction of the binding capacity to [3H]-QNB of approximately 40% was observed. Following exposure to soman by both acute and sub-acute inhalation exposure there was an increase in the apparent affinity (pD2) to ACh in the bronchial smooth muscle, due to the extensive inhibition of the AChE-activity. Inhalation of soman also induced a substantial inhibition of the AChE-activity in the lung (86%), but somewhat smaller inhibition in the hippocampus (70%) and almost no inhibition in the neostriatum (19%). Moreover, it was only in the lung where sub-acute exposure to soman produced a reduction of the binding capacity to [3H]-QNB and the reduction was approximately 50%. The results therefore show that after sub-acute inhalation of a relatively low concentration of the AChE-inhibitor soman, alterations in the number of cholinergic receptors are only observed in the peripheral cholinergic nervous system.

Acetylcholine↗
PubMed2006

Inhaled formaldehyde exposure: effect on bronchial response to mite allergen in sensitized asthma patients.

BACKGROUND: Formaldehyde, an indoor air pollutant, is known to be an irritant and an etiologic factor in occupational asthma. An epidemiologic study suggests that it may also increase the risk of childhood asthma for concentrations above 60 microg/m(3). AIM: To evaluate the influence of pre-exposure to low-dose formaldehyde (100 microg/m(3) in 30 min according to the World Health Organization's recommended maximum value for indoor environments) on bronchial response to Dermatophagoides pteronyssinus. METHOD: Nineteen asthmatic subjects were included. Each subject underwent a mite allergen bronchial challenge test immediately after a standardized exposure in a chamber to formaldehyde or air (random order). Induced sputum were collected 24 h before and after mite challenge. RESULTS: After formaldehyde inhalation, patients developed an immediate bronchial response at a significantly lower dose of mite allergen than after air exposure (the geometric mean PD(20) for Der p 1 was 34.3 ng after formaldehyde and 45.4 ng after placebo, P = 0.05). The late-phase reaction, expressed as the maximum fall in forced expiratory volume in 1 s (FEV(1)) from baseline, was significantly higher after formaldehyde (15%vs 11%, P = 0.046). CONCLUSION: Our study demonstrated that exposure to low levels of formaldehyde significantly enhanced bronchial responsiveness to mite allergen in mite-sensitized subjects with asthma.

Adult↗
PubMed2005

Health risk assessment on human exposed to environmental polycyclic aromatic hydrocarbons pollution sources.

To assess how the human exposure to environmental carcinogenic polycyclic aromatic hydrocarbons (PAHs) pollution sources generated from industrial, traffic and rural settings, we present a probabilistic risk model, appraised with reported empirical data. A probabilistic risk assessment framework is integrated with the potency equivalence factors (PEFs), age group-specific occupancy probability and the incremental lifetime cancer risk (ILCR) approaches to quantitatively estimate the exposure risk for three age groups of adults, children, and infants. The benzo[a]pyrene equivalents based PAH concentrations in rural, traffic, and industrial areas associated with age group-specific occupancy probability at different environmental settings are used to calculate daily exposure level through inhalation and dermal contact pathways. Risk analysis indicates that the inhalation-ILCR and dermal contact-ILCR values for adults follow a lognormal distribution with geometric mean 1.04x10(-4) and 3.85x10(-5) and geometric standard deviation 2.10 and 2.75, respectively, indicating high potential cancer risk; whereas for the infants the risk values are less than 10(-6), indicating no significant cancer risk. Sensitivity analysis indicates that the input variables of cancer slope factor and daily inhalation exposure level have the greater impact than that of body weight on the inhalation-ILCR; whereas for the dermal-ILCR, particle-bound PAH-to-skin adherence factor and daily dermal exposure level have the significant influence than that of body weight.

Adolescent↗
PubMed2001

A physiologically based pharmacokinetic model for methyl tert-butyl ether in humans: implementing sensitivity and variability analyses.

Methyl tert-butyl ether (MTBE) is added to gasoline to reduce carbon monoxide and ozone precursors from automobile emissions. The objectives of this study were to verify the ability of a physiologically based pharmacokinetic (PBPK) model to predict MTBE blood levels in humans and to investigate the effect of variability in the metabolism of MTBE and its influence on the predicted MTBE blood levels. The model structure for MTBE was flow-limited and had six essential compartments: lung, liver, rapidly perfused tissues, slowly perfused tissues, fat, and kidney. In this model, two pathways of metabolism are described to occur in the liver by Michaelis-Menten kinetics. Metabolic rate constants were measured in vitro using human liver microsomes and extrapolated to in vivo whole-body metabolism. Model predictions were compared with data on blood levels of MTBE taken from humans during and after a 1-h inhalation exposure to 1.7 ppm MTBE and after 4-h inhalation exposures to 4 or 40 ppm MTBE. The PBPK model accurately predicted MTBE pharmacokinetics at the high and low MTBE exposure concentrations for all time points. At the intermediate MTBE exposure concentration, however, the model underpredicted early time points while adequately predicting later time points. Results of the sensitivity analysis indicated that the influence of metabolic parameters on model output was dependent on MTBE exposure concentration. Subsequent variability analysis indicated that there was more variability in the actual measured MTBE blood levels than in the blood levels predicted by the PBPK model when using the range of metabolic parameters measured in vitro in human liver samples. By incorporating an understanding of the metabolic processes, this PBPK model can be used to predict blood levels of MTBE, which is important in determining target tissue dose estimates for risk assessment.

Administration, Inhalation↗
PubMed1993

Carcinogen-induced tissue vitamin A depletion. Potential protective advantages of beta-carotene.

Exposure to benzopyrene, an enzyme-inducing PAH carcinogen, promotes vitamin A depletion in exposed tissues. This effect is evident while on a vitamin A sufficient diet and without a decline in serum retinol. The finding of local tissue vitamin depletion without systemic depletion may have considerable implications in maintaining tissue health. While the described studies involved dietary exposure to benzopyrene, it is reasonable to extrapolate that inhalation exposure via cigarette smoke would have a similar effect in the lungs and perhaps stomach and bladder. Higher MFO enzyme activity in the lungs may have detrimental effects. Kellermann's early work identifying a higher incidence of lung cancer in those with genetically greater aryl hydrocarbon hydroxylase activity was interpreted as due to the greater formation of a reactive intermediate in the process of carcinogen metabolism. As an alternative hypothesis I suggest that those with higher enzyme inducibility may have greater carcinogen-induced vitamin A depletion. If poor tissue vitamin A nutriture potentiates the carcinogenicity of compounds such as benzopyrene, dietary or pharmacologic interventions which improve tissue nutriture could be important. The demonstrated effect of dietary beta-carotene on preventing carcinogen-induced tissue vitamin A depletion suggests one mechanism by which beta-carotene may be cancer protective. Further investigations are warranted, particularly with inhalation exposure to carcinogens and the effect of dietary beta-carotene on lung tissue nutriture.

Animals↗
PubMed2006

Effect of physical exertion on the biological monitoring of exposure of various solvents following exposure by inhalation in human volunteers: I. Toluene.

Physical exertion (work load) has been recognized as one of several factors that can influence the kinetics of xenobiotics within the human body. This study was undertaken to evaluate the impact of physical exertion on two exposure indicators of toluene (TOL) in human volunteers exposed under controlled conditions in an inhalation chamber. A group of four volunteers (one woman, three men) were exposed to TOL (50 ppm) according to the following scenarios involving several periods during which volunteers were asked to perform either aerobic (AERO), muscular (MUSC), or both (AERO/MUSC) types of physical exercise (exercise bicycle, treadmills, pulleys). The target intensities (W) for each exercising period of 30 min--interspaced with 15 min at rest--were the following: REST, 50 W AERO (time-weighted average intensity [TWAI]: 46 watts); 50 W AERO/MUSC (TWAI: 38 watts) and 100 W AERO (TWAI: 71 watts) for 7 hours and 50 W MUSC for 3 hours (TWAI: 29 watts). Alveolar air and urine samples were collected at different time intervals before, during, and after exposure for the measurement of unchanged TOL in expired air (TOL-A) and urinary o-cresol (o-CR). Overall, the results showed that TOL-A measured during and after all scenarios involving physical activities were higher (approximately 1.4-2.0 fold) compared with exposures at rest. All scenarios involving physical exertion also resulted in increased end-of-exposure urinary o-CR (mean +/- SD): 0.9 +/- 0.1 mg/L (REST) vs. 2.0 +/- 0.1 mg/L (TWAI 46 watts). However, exposure at a TWAI of 71 watts did not further increase o-CR excretion (1.7 +/- 0.2 mg/L). This study confirms the significant effect of work load on TOL kinetics and showed that o-CR excretion increased proportionally with work load expressed as TWAI or with the estimated mean pulmonary ventilation during the period of exposure. This study also shows that exposure to TOL (50 ppm) involving a work load of around 50 W (light intensity) or lower is likely to produce urinary o-CR values that clearly exceed the current biological exposure index value for TOL.

Adult↗
PubMed1991

[Data for substantiation of MPEL of 1,2,4-triazole in the workplace air].

1,2,4-Triazole belongs to the 3-d degree moderately dangerous compounds, according to the parameters of acute intragastric toxicity (LD50). Single and repeated applications of the substance on the skin of rats does not lead to local irritating or skin-resorptive effects. In the native state the substance produces moderate irritating effects on the eye mucosa of rabbits. It produces a moderately manifest cumulative effect of the functional character (Kcum greater than 5). 1,2,4-Triazole belongs to the 2-nd degree of danger according to LC50. The threshold of acute inhalational exposure (Li(mac)) 226.6 mg/m3, the threshold of chronic inhalational exposure (Lim(ch)), 19.8 mg/m3. The substance does not have mutagenic and embryotropic properties. 5 mg/m3 is recommended as the maximum allowable concentration for 1,2,4-triazole in the air of the working area.

Air Pollutants, Occupational↗
PubMed1995

A trichloroethylene risk assessment using a Monte Carlo analysis of parameter uncertainty in conjunction with physiologically-based pharmacokinetic modeling.

A Monte Carlo simulation is incorporated into a risk assessment for trichloroethylene (TCE) using physiologically-based pharmacokinetic (PBPK) modeling coupled with the linearized multistage model to derive human carcinogenic risk extrapolations. The Monte Carlo technique incorporates physiological parameter variability to produce a statistically derived range of risk estimates which quantifies specific uncertainties associated with PBPK risk assessment approaches. Both inhalation and ingestion exposure routes are addressed. Simulated exposure scenarios were consistent with those used by the Environmental Protection Agency (EPA) in their TCE risk assessment. Mean values of physiological parameters were gathered from the literature for both mice (carcinogenic bioassay subjects) and for humans. Realistic physiological value distributions were assumed using existing data on variability. Mouse cancer bioassay data were correlated to total TCE metabolized and area-under-the-curve (blood concentration) trichloroacetic acid (TCA) as determined by a mouse PBPK model. These internal dose metrics were used in a linearized multistage model analysis to determine dose metric values corresponding to 10(-6) lifetime excess cancer risk. Using a human PBPK model, these metabolized doses were then extrapolated to equivalent human exposures (inhalation and ingestion). The Monte Carlo iterations with varying mouse and human physiological parameters produced a range of human exposure concentrations producing a 10(-6) risk.

Administration, Inhalation↗
PubMed2002

Chemical respiratory allergy: role of IgE antibody and relevance of route of exposure.

Chemicals are able to cause various forms of allergic disease in susceptible individuals. Among those of greatest importance in the context of occupational disease is chemical respiratory allergy, where allergic sensitization of the respiratory tract is associated with elicitation of rhinitis, asthma and/or other pulmonary symptoms following inhalation exposure to the inducing chemical allergen. Although for some chemical respiratory allergens (including the acid anhydrides) there exists a strong correlation between symptoms and the presence of specific IgE antibody, for other respiratory sensitizers (and notably the diisocyanates) such an association is variable or absent. These data have resulted in speculation about a universal mandatory role for specific IgE antibody in the induction and elicitation of respiratory allergy to chemicals and of the nature of alternative or complementary mechanisms of sensitization. There is debate also regarding the routes through which exposure to relevant chemical allergens may result in the acquisition of respiratory sensitization. Although inhalation exposure is probably the most common and most important route through which allergic sensitization of the respiratory tract is achieved, there is evidence also that respiratory sensitization to chemicals may be acquired also by dermal contact; observations that have important implications for occupational health management. The significance of IgE antibody and dermal exposure in the context of occupational respiratory allergy to chemicals is discussed.

Animals↗
PubMed1984

In vivo genotoxicity and acute hepatotoxicity of 1,2-dichloroethane in mice: comparison of oral, intraperitoneal, and inhalation routes of exposure.

The in vivo genotoxicity of 1,2-dichloroethane (DCE) was studied in the liver of male C57BL/6 X C3H F1 (hereafter called B6C3F1) mice after single p.o., i.p., and inhalation exposures. The acute hepatotoxicity of DCE was also examined in order to determine nonnecrogenic exposure levels for each route of administration. Single-strand breaks and/or alkali-labile lesions were demonstrated by alkaline DNA-unwinding/hydroxylapatite chromatography in hepatic DNA at 4 hr after p.o. or i.p. administration of nonnecrogenic doses (100 mg/kg, p.o.; 150 mg/kg, i.p.) of DCE to groups of four to six mice. No evidence of hepatic DNA damage was found immediately following 4-hr inhalation exposures of mice to a nonnecrogenic (150 ppm) or necrogenic (500 ppm) concentration of DCE. Four-hr inhalation exposures of mice to concentrations of DCE causing high mortality within 24 hr (1000 to 2000 ppm) produced evidence of hepatic DNA damage at 4 hr, but the possibility that this damage was due to the acute necrogenic effects of the exposures could not be excluded. A significant fraction of the hepatic DNA damage observed 4 hr after i.p. administration of DCE (200 mg/kg) was still evident after 24 hr, indicating the persistence of unrepaired lesions in the DNA. These findings are consistent with the seemingly contradictory results of the two long-term carcinogenicity bioassays, in which DCE was found to be carcinogenic to Osborne-Mendel rats and B6C3F1, mice when administered by gavage but nontumorigenic to Sprague-Dawley rats and Swiss mice after chronic inhalation exposure. Therefore, our results provide additional evidence for the importance of a route of administration effect in the in vivo genotoxicity and carcinogenicity of DCE.

Administration, Intranasal↗
PubMed2001

Physiological modeling reveals novel pharmacokinetic behavior for inhaled octamethylcyclotetrasiloxane in rats.

Octamethylcyclotetrasiloxane (D4) is an ingredient in selected consumer and precision cleaning products. Workplace inhalation exposures may occur in some D4 production operations. In this study, we analyzed tissue, plasma, and excreta time-course data following D4 inhalation in Fischer 344 rats (K. Plotzke et al., 2000, Drug Metab. Dispos. 28, 192-204) to assess the degree to which the disposition of D4 is similar to or different from that of volatile hydrocarbons that lack silicone substitution. We first applied a basic physiologically based pharmacokinetic (PBPK) model (J. C. Ramsey and M. E. Andersen, 1984, Toxicol. Appl. Pharmacol. 73, 159-175) to characterize the biological determinants of D4 kinetics. Parameter estimation techniques indicated an unusual set of characteristics, i.e., a low blood:air (P(b:a) congruent with 0.9) and a high fat:blood partition coefficient (P(f:b) congruent with 550). These parameters were then determined experimentally by equilibrating tissue or liquid samples with saturated atmospheres of D4. Consistent with the estimates from the time-course data, blood:air partition coefficients were small, ranging from 1.9 to 6.9 in six samples. Perirenal fat:air partition coefficients were large, from 1400 to 2500. The average P(f:b) was determined to be 485. This combination of partitioning characteristics leads to rapid exhalation of free D4 at the cessation of the inhalation exposure followed by a much slower redistribution of D4 from fat and tissue storage compartments. The basic PK model failed to describe D4 tissue kinetics in the postexposure period and had to be expanded by adding deep-tissue compartments in liver and lung, a mobile chylomicron-like lipid transport pool in blood, and a second fat compartment. Model parameters for the refined model were optimized using single-exposure data in male and female rats exposed at three concentrations: 7, 70, and 700 ppm. With inclusion of induction of D4 metabolism at 700 ppm (3-fold in males, 1-fold in females), the parameter set from the single exposures successfully predicted PK results from 14-day multiple exposures at 7 and 700 ppm. A common parameter set worked for both genders. Despite its very high lipophilicity, D4 does not show prolonged retention because of high hepatic and exhalation clearance. The high lipid solubility, low blood:air partition coefficient, and plasma lipid storage with D4 led to novel distributional characteristics not previously noted for inhaled organic hydrocarbons. These novel characteristics were only made apparent by analysis of the time-course data with PBPK modeling techniques.

Administration, Inhalation↗
PubMed2005

Occupational exposure to aluminium phosphide and phosphine gas? A suspected case report and review of the literature.

The manufacture and application of aluminium phosphide fumigants pose risks of inhalation exposure to phosphine gas. This article presents a case report of suspected inhalation exposure to phosphine gas in a manufacturing facility for aluminium phosphide fumigants, which was associated with acute dyspnoea, hypotension, bradycardia and other signs of intoxication. These symptoms resolved within several hours after removal from exposure. A review of the data on human exposures to phosphide fumigants identifies both pesticide applicators and individuals in the vicinity of application to be at risk of accidental exposure and injury from phosphine inhalation. More recent reports have identified risks of phosphine gas inhalation in association with the clandestine production of methamphetamine. Toxicodynamic effects of phosphine result from the inhibition of cytochrome c oxidase and subsequent generation of reactive oxygen species. There remain unanswered questions relating to the toxicokinetics of phosphine, as well as the assessment of human exposure utilizing biomarkers. As initial signs and symptoms of intoxication from phosphine gas may be nonspecific and transient, there is a need for improved recognition of the potential hazards associated with phosphide fumigants and phosphine gas.

Administration, Inhalation↗
PubMed1998

Evaluation of octamethylcyclotetrasiloxane (D4) as an inducer of rat hepatic microsomal cytochrome P450, UDP-glucuronosyltransferase, and epoxide hydrolase: a 28-day inhalation study.

Repeated inhalation exposure to octamethylcyclotetrasiloxane (D4) produces a reversible and dose-related hepatomegaly and proliferation of hepatic endoplasmic reticulum in rats. However, the effects of D4 on the expression of cytochrome P450 enzymes have not been evaluated. In the present study, the time course for changes in hepatic microsomal cytochrome P450 enzyme expression following repeated inhalation exposure to D4 vapors was determined in male and female Fischer 344 rats. Animals were exposed to D4 vapor at concentrations of 70 and 700 ppm, via whole body inhalation for 6 h/day, 5 days/week for 4 weeks. Specified animals were euthanized on exposure days 3, 7, 14, 21, and 28. Microsomal fractions were prepared from fresh liver by differential centrifugation. Enzyme activity as well as immunoreactive protein levels of several cytochrome P450 enzymes (CYP), epoxide hydrolase, and UDP-glucuronosyltransferase (UDPGT) were evaluated. The time course for enzyme induction was monitored by measuring 7-ethoxyresorufin O-deethylase (EROD) and 7-pentoxyresorufin O-depentylase (PROD) activities on days 3, 7, 14, 21, and 28. CYP1A1/2 activity, as determined by EROD activity, was increased approximately 2- to 3-fold over the exposure period. However, an examination of immunoreactive protein revealed no induction of CYP1A1 and a suppression of CYP1A2 in the 700 ppm D4 group. In comparison, CYP2B1/2 enzyme activity, as determined by PROD, was significantly increased as early as day 3 in both the 70 and 700 ppm D4 groups of male and female rats. Overall, PROD activity on day 28 was induced more than 10-fold in the 70 ppm D4 groups and more than 20-fold in the 700 ppm D4 groups. The increase in PROD activity was paralleled by a comparable increase in CYP2B1/2 immunoreactive protein. There was a modest (2- to 3-fold) increase in CYP3A1/2 activity and immunoreactive protein, as determined by 6 beta-hydroxylation of testosterone and Western blot analysis. Expression of CYP enzymes was at or near maximum by day 14 and remained relatively constant throughout the exposure period. On day 28, epoxide hydrolase activity and immunoreactive protein were induced (2- to 3-fold) in a dose-dependent manner. Only slight changes in the expression and activity of UDPGT were detected, and these did not appear to be dose related. Thus, repeated inhalation exposure to D4 induces CYP enzymes and epoxide hydrolase in a manner similar to that observed for phenobarbital (PB). Therefore, D4 can be described as a "PB-like" inducer of hepatic microsomal enzymes in the Fischer 344 rat.

Adjuvants, Immunologic↗
PubMed2002

Safety assessment for hair-spray resins: risk assessment based on rodent inhalation studies.

The methods involved in the safety assessment of resins used in hair-spray products have received little peer review, or debate in the published literature, despite their widespread use, in both hairdressing salons and the home. The safety assessment for these resins currently involves determining the type of lung pathology that can be caused in animal inhalation exposure studies, and establishing the no-observable-effect level (NOEL) for these pathologies. The likely human consumer exposure is determined by techniques that model the simulated exposure under "in use" conditions. From these values it is then possible to derive the likely safety factors for human exposure. An important part of this process would be to recognize the intrinsic differences between rodents and humans in terms of the respiratory doses that each species experiences during inhalation exposures, for the purpose of the safety assessment. Interspecies scaling factors become necessary when comparing the exposure doses experienced by rats, compared to humans, because of basic differences between species in lung clearance rates and the alveolar area in the lungs. The rodent inhalation data and modeled human exposure to Resin 6965, a resin polymer that is based on vinyl acetate, has been used to calculate the safety factor for human consumer exposure to this resin, under a range of "in use" exposure conditions. The use of this safety assessment process clearly demonstrates that Resin 6965 is acceptable for human consumer exposure under the conditions considered in this risk assessment.

Animals↗
PubMed2004

Biochemical and behavioral effects of soman vapors in low concentrations.

Soman belongs to the most dangerous nerve agents because of the low effectiveness of the presently available antidotes. Soman acts by inhibiting acetylcholinesterase (AChE) both peripherally and centrally, with a subsequent accumulation of neuromediator acetylcholine and other metabolic changes. From the data published in literature it can be concluded that exposure to nerve agents leading to acute effects or chronic exposure to nerve agents may lead to delayed and persistent adverse effects. The aim of this study was to demonstrate changes in AChE and butyrylcholinesterase (BuChE) activities, stressogenic markers (i.e., tyrosine aminotransferase [TAT] activity, and plasma corticosterone level), and neuroexcitability and behavior 24 h and 4 wk following a single soman inhalation exposure at low level. AChE activity in erythrocytes and BuChE activity in plasma was decreased (dependent on the dose of soman) 24 h and 4 wk after the exposure. A similar decrease in AChE activity in different brain parts was observed. One of the stressogenic parameters, TAT, was changed 24 h after exposure only. Behavior of experimental animals was changed 24 h after the exposure, and 4 behavioral parameters persisted 4 wk after the exposure. Neuroexcitability was increased at 24 h after the exposure and had become about normal 4 wk after the exposure. Summarizing, long-term effects (4 wk) were observed after inhalation exposure of guinea pigs to sublethal concentrations of soman.

Acetylcholinesterase↗
PubMed1986

Biological effects of acetamide, formamide, and their monomethyl and dimethyl derivatives.

The industrial use of certain acetamides and formamides (particularly DMAC and DMF) for their solvent properties has resulted in rather extensive examination of their biological properties. Both DMAC and DMF are rapidly absorbed through biological membranes and are metabolized by demethylation first to monomethyl derivatives and then to the parent acetamide or formamide. Relatively high single doses to various species following oral, dermal, i.p., i.v., or inhalation exposures generally are required to produce mortality. The liver is the primary target following acute high level exposure, but massive doses can also produce damage to other organs and tissues. Repeated sublethal treatment by various routes also shows the liver to be the target organ with the degree of damage being proportional to the amount absorbed. With MMF, the potential usefulness as a cancer chemotherapeutic agent needs to be measured against the hepatotoxic effects produced in man. Acetamides and formamides are generally inactive in mutagenicity tests. Mammalian test systems do not appear to be genetically sensitive and DMF has been recommended for use as the vehicle in microbial assays designed to test for genetic activity of hard-to-dissolve chemicals. Embryotoxicity can be demonstrated at high doses; doses which generally show toxicity to the maternal animals. Structural abnormalities in sensitive species such as the rabbit are produced following exposure at near-lethal levels. The spectrum of abnormalities seen is broad and fails to show any time or site specificity in terms of developing organs/organ systems. Inhalation exposures to DMAC and DMF at levels producing some maternal toxicity in rats have produced no teratogenic response and only slight evidence of embryotoxicity. Long-term feeding of relatively high levels of acetamide produces liver cancer in rats. DMAC and DMF appear to be noncarcinogenic. The environmental toxicity of these chemicals is low. Liver damage can be produced by overexposure to these chemicals in man. Airborne concentrations need to be controlled and care should be taken to avoid excessive liquid contact as the chemicals are absorbed through the skin. A relationship exists between the amount of DMAC or DMF absorbed and the amount of MMAC or MMF excreted in the urine so that biomonitoring of the urinary metabolites can indicate situations in which total exposures, both dermal and inhalation, are excessive. An interaction between DMF and ethanol occurs such that signs, including severe facial flushing, appear when DMF-exposed individuals consume alcoholic beverages.

Acetamides↗
PubMed1989

A physiological model for simulation of benzene metabolism by rats and mice.

Studies conducted by the National Toxicology Program on the chronic toxicity of benzene indicated that B6C3F1 mice are more sensitive to the toxic effects of benzene than are F344 rats. A physiological model was developed to describe the uptake and metabolism of benzene in rats and mice and to determine if the observed differences in toxic effects could be explained by differences in the pathways for metabolism of benzene or by differences in uptake of benzene. Major pathways for elimination of benzene included metabolism to hydroquinone glucuronide or hydroquinone sulfate, phenyl glucuronide or phenyl sulfate, muconic acid, and prephenyl mercapturic acid or phenyl mercapturic acid. Model simulations for total benzene metabolized and for profiles of benzene metabolites were conducted for oral or inhalation exposure and compared to data for urinary excretion of benzene metabolites after exposure of rats and mice to [14C]- or [3H]-benzene by inhalation or gavage. Results for total amount of benzene metabolized, expressed per kilogram body weight, indicated that for inhalation exposure concentrations up to 1000 ppm, mice metabolized at least two to three times as much benzene as did rats. Simulations of oral exposure to benzene resulted in more benzene metabolized per kilogram body weight by rats at oral exposures of greater than 50 mg/kg. Patterns of metabolites formed after either route of exposure were very different for F344/N rats and B6C3F1 mice. Rats primarily formed the detoxification metabolite, phenyl sulfate. Mice formed hydroquinone glucuronide and muconic acid in addition to phenyl sulfate. Hydroquinone and muconic acid are associated with pathways leading to the formation of the putative toxic metabolites of benzene. Metabolic rate parameters, Vmax and Km, were very different for hydroquinone conjugate and muconic acid formation compared to formation of phenyl conjugates and phenyl mercapturic acids. Putative toxication pathways could be characterized as high affinity, low capacity whereas detoxification pathways were low affinity, high capacity. Model simulations suggested that for both rats and mice at lower exposure concentrations hydroquinone and muconic acid represented a larger fraction of the total benzene metabolized than at higher exposure concentrations where detoxification metabolites were predominant. Preferential production of a putative toxic metabolite at low exposure concentrations may have important implications in risk assessment for benzene.

Administration, Inhalation↗